The most common myelin disorder of the CNS is multiple sclerosis (MS), characterized by motor, sensory and cognitive impairments resulting from demyelinating lesions, considered to be initiated by transgression of immune constituents across blood-brain and cerebrospinal fluid (CSF) barriers. In active/demyelinating MS lesions, the numbers of mature OLs are comparable to the numbers in the NAWM, suggesting a relative preservation of OLs, in contrast to the significant loss in chronic lesions linked with disease progression8,9. Surviving OLs in acute lesions show “dying back” of processes with intact somas, suggesting sub-lethal injury that may precede their subsequent progressive loss10. This may be induced by systemic sources, such as fibrinogen11, that access the CNS via the blood-brain or CSF-brain barriers. In addition, there may be a contribution from local sources, including soluble products released by reactive microglia and astrocytes12–15 and the breakdown products of injured myelin16–18. Conversely, there could be lack of elements needed to maintain OL and myelin integrity (e.g., sources of energy, lipids)19. Discussed below in more detail are the potential mediators and mechanisms that underlie the above observations.
